Glycemic Control of Apoptosis in the Pancreatic Beta Cell: Danger of Extremes?

Excessive formation of oxygen radicals is a well-established mediator of hyperglycemic damage in diabetes to a wide range of tissues, such as neurons, retinal cells, and vascular endothelium. Increased oxygen radical formation is generally considered a toxic side effect of excessive rates of mitochondrial oxidative metabolism and electron transport in high glucose-exposed cells. Along the same line, metabolic oxidative stress is currently also regarded as crucial mediator of beta cell dysfunction and apoptosis under hyperglycemic conditions. Here the authors argue that a healthy beta cell is well equipped to deal adequately with elevated glucose metabolic rates, and demonstrate that decreased glucose catabolism leads to ROS production and apoptosis. They therefore propose that adverse metabolic conditions in poorly controlled diabetes (hyperglycemia and/or dyslipidemia) or genetic defects could decrease the viability of beta cells by interfering with normal glucose sensing and metabolism, rather than by overactivating it. This view is supported by the fragmentary data currently available on the pathways for hypergycemic and hypoglycemic beta cell death.